Despite APOE4 having the highest known risk for developing sporadic late-onset Alzheimer’s disease (AD), there is little information on how APOE4 variant impinges on the cellular functions of disparate cell types in the human brain, especially the astrocytes and microglia that are increasingly recognized to play essential roles in AD pathogenesis. Most genetic studies have relied on various mouse models expressing humanized APOE, thereby precluding direct inference of these findings and applicability to humans. Studies using human samples are confounded by different genetic backgrounds of different individuals and limited accessibility to various cultured cell types. In this talk, I will present our recent work using CRISPR/Cas9 genome editing tool to create isogenic APOE3 and APOE4 human iPSC lines that enable us to carry out comprehensive analysis of biochemical, cellular, and transcriptional impacts by APOE4 variant in multiple iPSC-derived brain cell types. We found that APOE3/APOE4 conversion significantly alters key functions of neurons and glial cells that together account for the many facets of AD pathology. Moreover, APOE4 organoids exhibited increased levels of p-tau and Aβ aggregates compared to those of APOE3. APOE4 variant significantly altered the transcriptomes of brain cell types, resulting in hundreds of differentially regulated genes, with the most affected involved in lipid metabolism, immune response, and AD pathology. We also identified remarkable concordance of APOE4-dependent gene expression between iPSC-derived brain cells and human AD brain samples, with expression of certain gene modules correlated well with clinical AD severity. Our findings underscore the multiphenotypic effects of APOE4 across multiple brain cell types to dramatically impact the developmental trajectory of AD pathology.